Reg (Regeneration gene) and Reg-related genes are members of a multi-gene family that is part of the calcium (C-type) dependent lectin superfamily. Members of the Reg family include: Reg I-alpha (REG1A), Reg I-beta (REG1B), REG-related sequence (RS), and pancreatitis associated protein (PAP; Miyashita et al., FEBS Lett. 377:429-433 (1995)). All of these genes are tandemly ordered in a 95-kb DNA region of 2p12. Recently, a new member of the Reg family, Reg IV, was isolated and characterized (Hartupee et al., Biochim. Biophys. Acta. 1518:287-293 (2001)). Reg IV is 30% identical and 50% homologous to Reg I and is mainly expressed in the pancreas, intestine, and colon. Studies have shown that Reg IV is significantly upregulated in a variety of disorders.
Reg IV MRNA, for instance, is significantly upregulated by mucosal injury from the inflammatory bowel diseases ulcerative colitis and Crohn's disease (Hartupee et al., Biochim. Biophys. Acta. 1518:287-293 (2001)). Inflammatory Bowel Disease (IBD) includes a number of chronic inflammatory disorders of the intestines. The two most common Inflammatory Bowel Diseases are ulcerative colitis and Crohn's disease. While both are inflammatory diseases of the bowel, there are several significant differences between ulcerative colitis and Crohn's disease. In ulcerative colitis, inflammation is confined to the inner lining (mucosa and/or submucosa) of the large intestine (colon and/or rectum), while in Crohn's disease inflammation extends beyond the inner lining and penetrates deeper layers of the intestinal wall of any part of the digestive system (esophagus, stomach, small intestine, large intestine, and/or anus). These disorders can cause painful, often life altering symptoms including, for example, diarrhea, cramping and rectal bleeding. Depending on the severity of these symptoms, patients may be unable to work or leave the home due to pain, fatigue, and the need for constant access to bathroom facilities. Accordingly, more effective treatments for inflammatory bowel disease would not only improve the health of vast numbers of people worldwide, but would also reduce the economic costs of these afflictions at the individual and societal level.
Reg proteins have also been shown to induce the proliferation of islet β-cells and to ameliorate the diabetes of 90% depancreatized rats and of non-obese diabetic mice (Watanabe, et al. PNAS U.S.A. 91:3589-3592 (1994); Gross et al., Endocrinology 139:2369-2374 (1998)). Over the past few decades, an increasing percentage of the population has become diabetic. Diabetes mellitus is categorized into two types: Type I, known as Insulin-Dependent Diabetes Mellitus (IDDM) or Type II, known as Non-Insulin-Dependent Diabetes Mellitus (NIDDM). IDDM is an autoimmune disorder in which the insulin-secreting pancreatic beta cells of the islets of Langerhans are destroyed. In these individuals, recombinant insulin therapy is employed to maintain glucose homeostasis and normal energy metabolism. NIDDM, on the other hand, is a polygenic disorder with no one gene responsible for the progression of the disease.
Insulin affects fat, muscle, and liver. Insulin is the major regulator of energy metabolism. Malfunctioning of any step(s) in insulin secretion and/or action can lead to many disorders, including for example the dysregulation of oxygen utilization, adipogenesis, glycogenesis, lipogenesis, glucose uptake, protein synthesis, thermogenesis, and maintenance of the basal metabolic rate. This malfunctioning results in diseases and/or disorders that include, but are not limited to, hyperinsulinemia, insulin resistance, insulin deficiency, hyperglycemia, hyperlipidemia, hyperketonemia, and diabetes. Numerous debilitating secondary effects include, but are not limited to, obesity, forms of blindness (cataracts and diabetic retinopathy), limb amputations, kidney failure, fatty liver, and coronary artery disease. Current drugs used to treat insulin resistance and/or diabetes (e.g., insulin secratogogues—sulfonylurea, insulin sensitizers—thiazolidenediones and metformin, and α-glucosidase and lipase inhibitors) are inadequate. Thus, more effective treatments for diabetes are needed.
PAP, REGIA, and REGIB are expressed in low levels in normal colonic epithelial cells, but elevated in 75% of tumors (Rechreche et al., Int. J. Cancer 81:688-694 (1999)). The most common gastrointestinal (GI) tract cancer in this country is cancer of the colon and rectum; followed by cancer of the pancreas. The most common tumor of the colon is adenomatous polyp. Primary lymphoma is rare in the colon and most common in the small intestine. Adenomatous polyps are the most common benign gastrointestinal tumors. They occur throughout the GI tract, most commonly in the colon and stomach, and are found more frequently in males than in females. They may be single, or more commonly, multiple, and sessile or pedunculated. They may be inherited, as in familial polyposis and Gardener's syndrome, which primarily involves the colon. Development of colon cancer is common in familial polyposis. Polyps often cause bleeding, which may occult or gross, but rarely cause pain unless complications ensue. Papillary adenoma, a less common form found only in the colon, may also cause electrolyte loss and mucoid discharge. A malignant tumor includes a carcinoma of the colon which may be infiltrating or exophytic and occurs most commonly in the rectosigmoid. Because the content of the ascending colon is liquid, a carcinoma in this area usually does not cause obstruction, but the patient tends to present late in the course of the disease with anemia, abdominal pain, or an abdominal mass or a palpable mass.
The prognosis with colonic tumors depends on the degree of bowel wall invasion and on the presence of regional lymph node involvement and distant metastases. The prognosis with carcinoma of the rectum and descending colon is quite unexpectedly good. Cure rates of 80 to 90% are possible with early resection before nodal invasion develops. For this reason, great care must be taken to exclude this disease when unexplained anemia, occult gastrointestinal bleeding, or change in bowel habits develop in a previously healthy patient. Complete removal of the lesion before it spreads to the lymph nodes provides the best chance of survival for a patient with cancer of the colon. Detection in an asymptomatic patient by occult-bleeding, blood screening results in the highest five year survival. Although colon and rectal cancers are currently treated with increasing rates of success, pancreatic cancer and other upper GI tract cancers (such as adenocarcinomas of the distal esophagus, stomach, bile ducts, liver, and duodenum) continue to induce high rates of mortality. The prognosis for persons with a GI tract adenocarcinoma, for example, is often very poor because these tumors are usually not detected early, grow aggressively, and are not particularly sensitive to chemotherapy. Hence, new and innovative treatments are urgently needed for both the most common, treatable GI tract cancers as well as the less common, usually fatal GI tract cancers.
Reg proteins have a variety of functions and are overexpressed in several disorders. There is a clear need, therefore, for identification and characterization of compositions, such as antibodies, that influence the biological activity of Reg proteins, both normally and in disease states. In particular, there is a need to isolate and characterize antibodies that modulate the biological activities of Reg IV for the treatment of gastrointestinal tract cancers, inflammatory bowel disease, and diabetes.